Compounds for improving mRNA splicing
Inventors
Slaugenhaupt, Susan A. • Johnson, Graham • Paquette, William D. • Zhang, Wei • Marugan, Juan
Assignees
General Hospital Corp • Curia Global Inc • US Department of Health and Human Services • Government of the United States of America
Publication Number
US-11702417-B2
Publication Date
2023-07-18
Expiration Date
2036-01-15
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Abstract
Provided herein are compounds useful for improving mRNA splicing in a cell. Exemplary compounds provided herein are useful for improving mRNA splicing in genes comprising at least one exon ending in the nucleotide sequence CAA. Methods for preparing the compounds and methods of treating diseases of the central nervous system are also provided.
Core Innovation
The invention provides compounds useful for improving mRNA splicing in a cell, particularly in genes comprising at least one exon ending in the nucleotide sequence CAA. The compounds include various kinetin derivatives represented by Formula (I) and Formula (II), along with pharmaceutically acceptable salts thereof. The application also discloses methods for preparing these compounds and treating diseases of the central nervous system associated with mRNA splicing defects.
The problem addressed is the need for therapeutic agents that can improve mRNA splicing defects, such as those caused by mutations leading to tissue-specific exon skipping, exemplified by familial dysautonomia (FD). FD is caused by mutations in the IKBKAP gene resulting in aberrant splicing and associated severe sensory and autonomic neuropathies. Prior treatments with kinetin required high doses to achieve splicing correction, limiting their therapeutic utility. Thus, the invention aims to provide compounds that effectively target mRNA splicing mechanisms with improved potency and therapeutic potential.
Claims Coverage
The patent includes two independent claims covering compounds of Formula (Ic) and a related structure, focusing on their chemical features and therapeutic methods.
Compounds for improving mRNA splicing
Compounds of Formula (Ic) and related structures with specified substituent groups designed to improve mRNA splicing, particularly in genes with exons ending in CAA.
Pharmaceutical compositions comprising the compounds
Formulations containing the compounds of Formula (Ic), or related compounds, along with pharmaceutically acceptable carriers.
Methods of treating familial dysautonomia
Use of the compounds in therapeutically effective amounts to reduce or alleviate symptoms of familial dysautonomia in subjects in need thereof.
The claims cover novel compounds with defined chemical structures, pharmaceutical compositions containing these compounds, and methods of treating familial dysautonomia by administering these compounds, emphasizing their capacity to improve mRNA splicing and treat diseases caused by splicing defects.
Stated Advantages
Certain provided compounds can improve mRNA splicing at lower doses than kinetin, enhancing efficacy.
Compounds demonstrate therapeutic potential for treatment of familial dysautonomia and other diseases related to mRNA splicing defects.
The compounds improve exon inclusion in genes with splicing defects, including in central nervous system tissues.
Documented Applications
Treatment of diseases associated with mRNA splicing defects, particularly familial dysautonomia.
Therapeutic use in diseases of the central nervous system including but not limited to amyotrophic lateral sclerosis, autism spectrum disorders, Charcot-Marie-Tooth disease, dementia, epilepsy, Huntington's disease, Marfan syndrome, muscular dystrophies, neurofibromatosis 1, Parkinson's disease, retinoblastoma, schizophrenia, and tuberous sclerosis.
Improvement of mRNA splicing in genes having exons ending in the nucleotide sequence CAA, and increasing inclusion of normally skipped exons.
Use in methods to increase IKAP protein expression and WT IKBKAP mRNA levels in cells and patients.
Combination therapies with other pharmaceutical agents such as phosphatidylserine for treatment of familial dysautonomia.
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